Radioactive holmium-166 loaded poly-(L)-lactic acid (PLLA) microspheres have been proposed as a promising new treatment for liver malignancies in the early 1990's (Mumper et al., J. Nucl. Med. 1991, 32, 2139-2143). Since then these microspheres have been studied extensively (Nijsen et al., Eur. J. Nucl. Med. 1999, 26, 699-704; Nijsen et al., Biomaterials 2001, 22 3073-3081; Zielhuis et al., Biomaterials 2005, 26, 925-932; and Zielhuis et al., Biomacromolecules 2006, 7, 2217-2223). 166Ho (166-holmium) is a combined beta and gamma emitter. These radioactive microspheres have superior physical and chemical properties than the currently available 90Y (90-yttrium) microspheres (Murthy et al., Radiographics 2005, 25 Suppl. 1, S41-S55). The holmium loaded microspheres can, for instance, be imaged directly using nuclear imaging, due to the gamma radiation that 166Ho emits, and MR imaging, due to the high paramagnetic value (x value) of holmium.
The holmium loaded PLLA (poly-(L-lactic acid)) microspheres can be prepared by incorporating holmium acetylacetonate into poly(L)-lactic acid by way of solvent evaporation. The stability of the microspheres so obtained is believed to be the result of the interaction of the carbonyl groups of poly-(L)-lactic acid with the Ho-ion in the holmium acetylacetonate complex (Nijsen et al., Biomaterials 2001, 22 3073-3081). The poly-(L)-lactic acid thus functions as a binder or stabiliser for the formation of the microspheres.
A disadvantage to holmium loaded PLLA microspheres is the limited loading capacity of these microspheres. The average holmium loading of these microspheres is around 17 wt. % (w/w) (Nijsen et al., Biomaterials 2001, 22 3073-3081 and Zielhuis et al., Biomaterials 2005, 26, 925-932).
Microspheres with substantially higher content of lanthanide metal are disclosed in WO-A-2009/011589. In accordance with the invention disclosed therein the microspheres with high lanthanide metal content are prepared using a lanthanide metal organic compound, while no binder or only very small amounts of binder such as poly-(L)-lactic acid is used. The lanthanide ions form a complex with a number of organic molecules, such as acetylacetonate, 3,5-heptanedione, and/or 2-(acetoacetoxyethyl)methacrylate. The invention of WO-A-2009/011589 shows that the reduction of binder material does not lead to a disintegration of the microspheres. Instead, the resulting microspheres are highly stable and contain a high amount of lanthanide while no (or hardly any) binder is needed. Accordingly, microspheres having a lanthanide metal content of more than 20 wt. %, based on total microsphere, can be prepared. These microspheres have a number of advantages, including a shorter neutron activation time and higher specific activity. This in turn leads to a reduced amount of microspheres to be administered to patients and improved MRI (magnetic resonance imaging) signals.
It would, however, be desirable to design microspheres wherein the ligands complexing with the lanthanide metal are based on compounds naturally occurring in the body, so that, when applied to a patient, possible toxic effects of the microspheres are minimized.
Objective of the invention is to meet this existing need in the art and provide improved lanthanide metal microspheres.
The inventors found that this objective can, at least in part, be met by providing lanthanide metal nanospheres or microspheres wherein the lanthanide is present in a specific different complex.